The Nationals fell behind 3-0 while being held in check through four innings by Mets starter Oliver Perez. But Washington's weak offense - 3.5 runs per game and a major league-low .227 batting average coming in - broke out for three runs in the fifth, four in the sixth and three in the seventh.
And Lopez led the way, twice coming through with the bases loaded. He put the Nationals on the scoreboard with his single off Perez (2-1) in the fifth, making it 3-2, then broke a tie in the sixth with his first homer of the season, off reliever Aaron Heilman.
Washington finished with 13 hits and made a winner of Mike O'Connor (1-0), who made his first appearance in the majors since 2006 after being called up from Triple-A Columbus before the game.
O'Connor pitched one inning of one-hit ball in relief of Shawn Hill, who departed after giving up three runs through five innings.
Each run allowed by Hill came on a two-out single - by Perez, Ryan Church and Luis Castillo.
But that lead evaporated in the fifth, when Washington filled the bases with no outs on two walks and a single, then scored on Lopez's hit and Ryan Zimmerman's RBI groundout.
In the sixth, Perez put two men on and then, with two outs, Heilman entered. The reliever walked pinch-hitter Lastings Milledge - he was a late scratch for Washington, though the team didn't say why - and that brought up Lopez.
A 2005 All-Star with Cincinnati, he hit .245 last season, then lost out to second baseman Ronnie Belliard and shortstop Cristian Guzman in a three-way competition for the two middle infield spots during spring training this year.
But Lopez moved into the starting lineup a week ago, taking over for Belliard at second base, and also has supplanted Guzman as the leadoff hitter. Belliard entered Thursday batting .214, and manager Manny Acta has been desperate to get more offense.
With the count full, Lopez drove the ball over the out-of-town scoreboard in right-center, clapping and screaming as he rounded first, then smacking third-base coach Tim Tolman's hand hard while turning for home. It was Lopez's fourth career grand slam, and the Nationals' first of the season. He's driven in six runs in a game three times, once last season.
In his past seven games, all as a starter, Lopez is 10-for-28 (.357) with seven RBIs and six runs.
Perez was charged with five runs and six hits in 5 2-3 innings. Heilman's line was worse: two runs and three hits in 1-3 of an inning. He was followed by Jorge Sosa, who gave up three runs - one earned - and three hits in one inning.
The Mets were content to play small ball early, then had Carlos Beltran and Marlon Anderson hit solo shots late.
